Proteasome-dependent inactivation of Akt is essential for 12-O-tetradecanoylphorbol 13-acetate-induced apoptosis in vascular smooth muscle cells.
Apoptosis of vascular smooth muscle cells (SMCs) is a prominent feature of blood vessel remodeling. Here we investigated the effect of 12-O-tetradecanoylphorbol 13-acetate (TPA) on SMC apoptosis. We found that TPA treatment induced SMC apoptosis through the rapid downregulation of Akt phosphorylation. The inhibition of Akt activation by TPA was markedly reduced by inhibitors of protein phosphatase 2A and proteasome. Moreover, TPA promoted the ubiquitination of p-Akt, whereas inhibition of TPA-induced PKC activation suppressed the downregulation and ubiquitination of p-Akt. Taken together, these results demonstrate that TPA triggers inactivation of Akt, at least in part, through PKC and Ubiquitin-proteasome degradation, thereby contributing to SMC apoptosis.
Fan
Yongna
Y
Department of Pathology and National Laboratory of Medical Molecular Biology, Peking Union Medical College, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Tsinghua University, Beijing 100005, China.
Xie
Ping
P
Zhang
Hua
H
Guo
Shubin
S
Gu
Dongfeng
D
She
Mingpeng
M
Li
HuiHua
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D002273:Carcinogens; D004791:Enzyme Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D046988:Proteasome Endopeptidase Complex; D013755:Tetradecanoylphorbol Acetate